Triazoles as farnesyl transferase inhibitors

ABSTRACT

a prodrug, N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof, wherein L 1  and L 2  are R 1 —Y— wherein each (R 1 —Y)— substituent is defined independently of the other; Y is C 1-4 alkanediyl, C 2-4 alkenediyl, C 2-4 alkynediyl, C(═O), or a direct bond; R 1  is hydrogen, cyano, aryl or a substituted or unsubstituted C 1-14 heterocycle; ═Z 1 —Z 2 ═Z 3 — represents a radical of formula ═N—N═CH— (a-1), ═N—CH═N— (a-2), ═CH—N═N— (a-3); X is SO 2 , (CH 2 ), wherein n is 1 to 4, C(═O), C(═S), or a direct bond; R 2  is aryl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more substituents independently selected from hydroxy, aryl, aryloxy, a substituted or unsubstituted C 1-14 heterocycle, C 3-7 cycloalkyl, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkyloxy, hydroxyC 1-6 alkylthio and arylC 1-6 alkylthio, C 1-12 alkyl or C 1-12 alkyl substituted with one or more substituents independently selected from hydroxy, aryl, aryloxy, a substituted or unsubstituted C 1-14 heterocycle, C 3-7 cycloalkyl, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkyloxy, hydroxyC 1-6 alkylthio and arylC 1-6 alkylthio; R 3  is aryl, —NR 5 R 6 , a substituted or unsubstituted C 1-14 heterocycle, or C 2-4 alkenediyl substituted with a substituted or unsubstituted C 1-14 heterocycle or aryl; R 4  is hydrogen, aryl, C 3-7 cycloalkyl, C 1-6 alkyl or C 1-6 alkyl substituted with C 3-7 cycloalkyl, hydroxycarbonyl, C 1-4 alkyloxycarbonyl or aryl; R 5  and R 6  are each independently selected from hydrogen, a substituted or unsubstituted C 1-14 heterocycle, aryl, C 1-12 alkyl and C 1-12 alkyl substituted with one or more substituents selected from hydroxy, aryl, aryloxy or a substituted or unsubstituted C 1-14 heterocycle.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of prior application U.S. Ser. No.11/143,814 filed on Jun. 2, 2005, which is a division of applicationSer. No. 10/130,322, May 13, 2002, which is a 371 of applicationPCT/EP00/11393 filed on Nov. 15, 2000, now U.S. Pat. No. 7,049,324,which claims priority from U.S. Provisional Patent Application60/165,434 filed on Nov. 15, 1999. These applications are incorporatedherein by reference.

The present invention is concerned with triazole derivatives, thepreparation thereof, pharmaceutical compositions comprising said novelcompounds and the use of these compounds as a medicine as well asmethods of treatment by administering said compounds.

Oncogenes frequently encode protein components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer. A particular groupof oncogenes is known as ras which have been identified in mammals,birds, insects, mollusks, plants, fungi and yeasts. The family ofmammalian ras oncogenes consists of three major members (“isoforms”):H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highlyrelated proteins generically known as p21^(ras). Once attached to plasmamembranes, the mutant or oncogenic forms of p21^(ras) will provide asignal for the transformation and uncontrolled growth of malignant tumorcells. To acquire this transforming potential, the precursor of thep21^(ras) oncoprotein must undergo an enzymatically catalyzedfarnesylation of the cysteine residue located in ahydroxycarbonyl-terminal tetrapeptide. Therefore, inhibitors of theenzymes that catalyzes this modification, i.e. farnesyl transferase,will prevent the membrane attachment of p21^(ras) and block the aberrantgrowth of ras-transformed tumors. Hence, it is generally accepted in theart that farnesyl transferase inhibitors can be very useful asanticancer agents for tumors in which ras contributes to transformation.

Attachment of the p21^(ras) oncoproteins to the plasma membranes canalso be the result of geranylgeranyltransferase I (GGTase I) activity.GGTase I attaches the lipid geranylgeranyl to the ras oncoproteins andas such provides a signal for the transformation and uncontrolled growthof malignant tumor cells. Hence, it is generally accepted in the artthat geranylgeranyltransferase inhibitors can be very useful asanticancer agents for tumors in which ras contributes to transformation.

Since mutated oncogenic forms of ras are frequently found in many humancancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has beensuggested that farnesyl tranferase and/or geranylgeranyltransferaseinhibitors can be very useful against these types of cancer.

More recent studies have demonstrated that farnesyl protein transferaseinhibitors have antitumor activity which extends beyond tumors havingras mutations (Sepp-Lorenzino et al., Cancer Res. Vol 55, 5302-5309,1995). This additional activity may derive from effects on rhoBfarnesylation (Du et al., Molec. Cell. Biol. Vol 19, 1831-1840, 1999) orfrom inhibition of the function of other farnesylated proteins.Regardless of the mechanism, these agents appear to have therapeuticutility in cancer and other proliferative disorders.

It is, therefore, an object of this invention to provide a novel classof peptidomimetic FPTase inhibitors which are capable to inhibitprenylation of proteins, such as Ras, both at the enzymatic and cellularlevel.

The present invention concerns compounds of formula (I)

a prodrug, N-oxide, addition salt, quaternary amine or stereochemicallyisomeric form thereof, whereinL¹ and L² are R¹—Y— wherein each (R¹—Y)— substituent is definedindependently of the other;Y is C₁₋₄alkanediyl, C₂₋₄alkenediyl, C₂₋₄alkynediyl, C(═O), or a directbond;R¹ is hydrogen, cyano, aryl or a substituted or unsubstitutedC₁₋₁₄heterocycle;═Z¹—Z²═Z³— represents a radical of formula═N—N═CH—  (a-1)═N—CH═N—  (a-2)═CH—N═N—  (a-3)X is SO₂, (CH₂)_(n) wherein n is 1 to 4, C(═O), C(═S), or a direct bondR² is aryl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl substituted with one or moresubstituents independently selected from hydroxy, aryl, aryloxy, asubstituted or unsubstituted C₁₋₁₄heterocycle, C₃₋₇cycloalkyl,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl,hydroxyC₁₋₆alkyloxy, hydroxyC₁₋₆alkylthio and arylC₁₋₆alkylthio,C₁₋₁₂alkyl or C₁₋₁₂alkyl substituted with one or more substituentsindependently selected from hydroxy, aryl, aryloxy, a substituted orunsubstituted C₁₋₁₄heterocycle, C₃₋₇cycloalkyl, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkyloxy,hydroxyC₁₋₆alkylthio and arylC₁₋₆alkylthio;R³ is aryl, —NR⁵R⁶, a substituted or unsubstituted C₁₋₁₄heterocycle, orC₂₋₄alkenediyl substituted with a substituted or unsubstitutedC₁₋₁₄heterocycle or aryl;R⁴ is hydrogen, aryl, C₃₋₇cycloalkyl, C₁₋₆alkyl or C₁₋₆alkyl substitutedwith C₃₋₇cycloalkyl, hydroxycarbonyl, C₁₋₄alkyloxycarbonyl or aryl;R⁵ and R⁶ are each independently selected from hydrogen, a substitutedor unsubstituted C₁₋₁₄heterocycle, aryl, C₁₋₁₂alkyl and C₁₋₁₂alkylsubstituted with one or more substituents selected from hydroxy, aryl,aryloxy or a substituted or unsubstituted C₁₋₁₄heterocycle;R⁷ is substituted or unsubstituted phenyl, —NR⁸R⁹ or a substituted orunsubstituted C₁₋₁₄heterocycle;R⁸ and R⁹ are independently selected from hydrogen, substituted orunsubstituted phenyl, C₃₋₆cycloalkyl, a substituted or unsubstitutedC₁₋₁₄heterocycle, C₁₋₆alkyl and C₁₋₆alkyl substituted with one or moresubstituents independently selected from C₁₋₄alkyloxycarbonyl,hydroxycarbonyl, substituted or unsubstituted phenyl and a substitutedor unsubstituted C₁₋₁₄heterocycle;aryl, as a group or part of a group, is naphthyl or phenyl each of whichmay optionally be substituted with one or more substituents selectedfrom trifluoromethyl, trifluoromethyloxy, halo, cyano, nitro,C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, phenylC₁₋₆alkyl, phenylC₁₋₆alkyloxy,phenyloxy, phenylcarbonyl, hydroxycarbonyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino,mono- or di(C₁₋₄alkyl)amino wherein said C₁₋₄alkyl is substituted withone or more substituted or unsubstituted phenyl, S(O)₂—R⁷,C₁₋₆alkylcarbonylamino, substituted or unsubstituted phenyl, and asubstituted or unsubstituted C₁₋₁₄heterocycle.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₄alkyl as a group or part of a groupdefines straight and branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl,butyl, 1-methylethyl, 2-methylpropyl and the like; C₁₋₆alkyl as a groupor part of a group includes C₁₋₄alkyl and the higher homologues thereofhaving 5 to 6 carbon atoms such as, for example, pentyl, 2-methyl-butyl,hexyl, 2-methylpentyl and the like; C₁₋₁₂alkyl as a group or part of agroup includes C₁₋₄alkyl, C₁₋₆alkyl and the higher homologues thereofhaving 7 to 12 carbon atoms such as, for example heptyl, octyl, nonyl,decyl, undecyl, dodecyl and the like; C₁₋₄alkanediyl as a group or partof a group defines bivalent straight and branched chained saturatedhydrocarbon radicals having from 1 to 4 carbon atoms, such as, forexample, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl andthe branched isomers thereof; C₂₋₄alkenyl as a group or part of a groupdefines straight and branched chain hydrocarbon radicals containing onedouble bond and having from 2 to 4 carbon atoms such as, for example,ethenyl, 2-propenyl, 3-butenyl and the like; C₂₋₄alkenediyl as a groupor part of a group defines bivalent straight and branched chainhydrocarbon radicals containing one double bond and having from 2 to 4carbon atoms such as, for example, ethenediyl, 2-propenediyl,3-butenediyl and the like; C₂₋₄alkynyl as a group or part of a groupdefines straight and branched chain hydrocarbon radicals containing onetriple bond and having from 2 to 4 carbon atoms such as, for example,ethynyl, 2-propynyl, 3-butynyl and the like; C₂₋₄alkynediyl as a groupor part of a group defines bivalent straight and branched chainhydrocarbon radicals containing one triple bond and having from 2 to 4carbon atoms such as, for example, ethynediyl, 2-propynediyl,3-butynediyl and the like; C₃₋₇cycloalkyl is defined as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “C(═O)”refers to a carbonyl and “SO₂” to a sulfon.

The term C₁₋₁₄heterocycle defines one or more rings (including 3, 4, 5or 6 membered heterocyclic rings) which may be independently saturated,partially saturated, unsaturated, including aromatic, containing 1 to 14carbon atoms and one or more (for example 1, 2, 3 or 4) heteroatomsselected from N, O and S. Examples of such groups include1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, benzodioxolanyl,benzodioxolyl, benzofuranyl, benzopyranyl, benzopyridinyl,benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,dihydrobenzofuranyl, dihydropyrimidinyl, dioxanyl, dioxolanyl,dithianyl, furanyl, imidazo[2,1-b]thiazolyl, imidazolinyl, imidazolyl,indanyl, indolinyl, indolyl, isobenzofuranyl, isobenzothienyl,isoindolyl, isoquinolinyl, isoquinolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolopyridinyl,oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl,pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrazolyl, thiadiazolyl, thiazolinyl, thiazolopyridinyl, thiazolyl,thienyl, thiolanyl, thiomorpholinyl, triazinyl, triazolyl,triazospirodecanyl or trithianyl.

Suitably, C₁₋₁₄heterocycle includes triazolyl, thienyl, quinolinyl,benzothiazolyl, quinoxalinyl, imidazolyl, benzimidazolyl, pyridinyl,pyrimidinyl, pyridazinyl, furanyl, benzofuranyl, furanyl,dihydrobenzofuranyl, benzopyranyl, benzothienyl, pyrrolidinyl, indanyl,benzodioxolanyl, morpholinyl, pyrazinyl and triazinyl.

Said C₁₋₁₄heterocycle may be substituted with one or more substituentsselected from substituted or unsubstituted phenyl, trifluoromethyl,trifluoromethyloxy, halo, hydroxy, cyano, nitro, C₁₋₁₂alkyl,C₁₋₁₂alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, amino,aminocarbonyl, furanyl, mono- or di(C₁₋₄alkyl)amino, thienyl, pyridinyl,mono- or di(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkylcarbonylamino, substitutedor unsubstituted phenylsulfonyl, substituted or unsubstitutedphenylcarbonyl and C₁₋₁₂alkyl substituted with one or more substituentsselected from substituted or unsubstituted phenyl, pyrazinyl, furanyland thienyl

The term substituted phenyl particularly includes phenyl substitutedwith one or more substituents selected from trifluoromethyl,trifluoromethyloxy, halo, hydroxy, cyano, nitro, C₁₋₁₂alkyl,C₁₋₁₂alkyloxy, phenylC₁₋₆alkyl, phenylC₁₋₆alkyloxy, phenyloxy,phenylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, amino, mono- ordi(C₁₋₄alkyl)amino, mono- or di(phenyl)amino, C₁₋₆alkylcarbonylamino orphenyl.

In a preferred embodiment of the invention, the group

is positioned on the second carbon atom of the triazole ring of formula(I).

As used herein before, the term “one or more” covers the possibility ofall the available C-atoms, where appropriate, to be substituted,preferably 1, 2 or 3.

The term prodrug as used throughout this text means thepharmacologically acceptable derivatives, e.g. esters and amides, suchthat the resulting biotransformation product of the derivative is theactive drug as defined in the compounds of formula (I). The reference byGoodman and Gilman (The Pharmacological Basis of Therapeutics, 8^(th)ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. 13-15)describing prodrugs generally, is hereby incorporated.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

It will be appreciated that some of the compounds of formula (I) andtheir prodrugs, N-oxides, addition salts, quaternary amines andstereochemically isomeric forms may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their prodrugs, N-oxides, addition salts, quaternary amines maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure as wellas each of the individual isomeric forms of formula (I) and theirprodrugs, N-oxides, salts, solvates or quaternary amines substantiallyfree, i.e. associated with less than 10%, preferably less than 5%, inparticular less than 2% and most preferably less than 1% of the otherisomers. Stereochemically isomeric forms of the compounds of formula (I)are obviously intended to be embraced within the scope of thisinvention.

References to alkenyl groups, include groups which may be in the E or Zform or a mixture thereof.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butane-dioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the prodrugs, N-oxides, addition salts, quaternaryamines and all stereoisomeric forms.

The present invention further includes the compounds of formula (I)wherein one or more of the following restrictions apply:

-   a) Y is C₁₋₄alkanediyl, or a direct bond; or-   b) R¹ is hydrogen, cyano, aryl or a substituted or unsubstituted    C₁₋₁₄heterocycle; or-   c) ═Z¹—Z²═Z³— is a radical of formula (a-1) or (a-2), in particular    (a-1); or-   d) R² is aryl, C₃₋₇cycloalkyl, C₁₋₁₂alkyl or C₁₋₁₂alkyl substituted    with one or more substituents selected from hydroxy, aryl, aryloxy,    substituted or unsubstituted C₁₋₁₄heterocycle, hydroxycarbonyl,    hydroxyC₁₋₆alkyloxy, or arylC₁₋₆alkylthio; or-   e) R³ is aryl; —NR⁵R⁶; substituted or unsubstituted C₁₋₁₄heterocycle    or C₂₋₄alkenediyl substituted with one or more substituents selected    from aryl, and a substituted or unsubstituted C₁₋₁₄heterocycle (in a    preferred embodiment said substituted or unsubstituted    C₁₋₁₄heterocycle is selected from triazolyl, thienyl, quinolinyl,    benzothiazolyl, quinoxalinyl, imidazolyl, benzimidazolyl, pyridinyl,    pyrimidinyl, pyridazinyl, furanyl, benzofuranyl, furanyl,    dihydrobenzofuranyl, benzopyranyl, benzothienyl, pyrrolidinyl,    indanyl, benzodioxolanyl, morpholinyl and triazinyl); or-   f) R⁴ is hydrogen or C₁₋₆alkyl; or-   g) R⁵, R⁶, R⁷, R⁸, R⁹, or X are defined as above.

Another aspect of this invention consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   a) L¹ is R¹—Y— wherein R¹ is hydrogen, substituted or unsubstituted    phenyl (in a preferred embodiment said substituted phenyl is    substituted with one or more substituents selected from halo, nitro,    cyano, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₆alkyloxycarbonyl,    trifluoromethyl, trifluoromethyloxy, and phenyloxy), benzodioxolyl,    pyridinyl or pyridinyl substituted with one or more substituents    selected from C₁₋₆alkyl, hydroxy, halo, cyano, and    C₁₋₆alkyloxycarbonyl and wherein Y is C₁₋₄alkanediyl or a direct    bond; or-   b) L² is R¹—Y— wherein R¹ is hydrogen, cyano, substituted or    unsubstituted phenyl (in a preferred embodiment said substituted    phenyl is substituted with one or more substituents selected from    halo, nitro, cyano, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₆alkyloxycarbonyl,    trifluoromethyl, trifluoromethyloxy, and phenyloxy) and wherein Y is    C₁₋₄alkanediyl or a direct bond; or-   c) ═Z¹—Z²═Z³— is a radical of formula (a-1);-   d) X is SO₂, C(═O) or a direct bond; or-   e) R² is aryl or C₁₋₁₂alkyl wherein C₁₋₁₂alkyl may optionally be    substituted with one or more substituents selected from aryl and a    substituted or unsubstituted C₁₋₁₄heterocycle; or-   f) R³ is aryl, a substituted or unsubstituted C₁₋₁₄heterocycle, or a    C₂₋₄alkenediyl substituted with one or more aryl; or-   g) R⁴ is hydrogen; or-   h) R⁵, R⁶, R⁷, R³ or R⁹ are defined as above.

Another group of compounds of formula (I), are compounds of formula

or their prodrugs, N-oxides, addition salts, quaternary amines andstereochemically isomeric forms, whereinX is SO₂, (CH₂)_(n), C(═O) or a direct bond;Y is C₁₋₄alkanediyl, C₂₋₄alkenediyl, C₂₋₄alkynediyl or C(═O);═Z¹—Z²═Z³— represents a radical of formula═N—N═CH—  (a-1)═N—CH═N—  (a-2) or═CH—N═N—  (a-3);n is 1 to 4;R¹ is aryl or a substituted or unsubstituted C₁₋₁₄heterocycle;R² is aryl, C₃₋₇cycloalkyl or C₁₋₁₂alkyl wherein C₃₋₇cycloalkyl andC₁₋₁₂alkyl may optionally be substituted with 1 or more substituentsselected from hydroxy, aryl, aryloxy, a substituted or unsubstitutedC₁₋₁₄heterocycle, C₃₋₇cycloalkyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkyloxy, hydroxyC₁₋₆alkylthio orarylC₁₋₆alkylthio;R³ is aryl or substituted or unsubstituted C₁₋₁₄heterocycle;R⁴ is hydrogen, aryl, C₃₋₇cycloalkyl or C₁₋₆alkyl optionally substitutedwith C₃₋₇cycloalkyl, hydroxycarbonyl, C₁₋₄alkyloxycarbonyl or aryl;aryl is naphthyl or phenyl each of which may optionally be substitutedwith one or more substituents selected from trifluoromethyl,trifluoromethyloxy, halo, cyano, nitro, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy,phenylC₁₋₆alkyl, phenylC₁₋₆alkyloxy, phenyloxy, phenylcarbonyl,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, amino, mono- ordi(C₁₋₄alkyl)amino, C₁₋₆alkylcarbonylamino, substituted or unsubstitutedphenyl or a C₁₋₁₄heterocycle.

A group of interesting compounds consists of those compounds of formula(I-a) wherein one or more of the following restrictions apply:

Y is C₁₋₄alkanediyl, C₁₋₄alkynediyl or C(═O);

═Z¹—Z²═Z³— is a radical of formula (a-1) or (a-2), in particular (a-1);

R¹ is phenyl, benzodioxolyl or pyridinyl wherein said phenyl mayoptionally be substituted with one or more substituents selected fromhalo, nitro, cyano, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₆alkyloxycarbonyl,trifluoromethyl; and wherein said pyridinyl may optionally besubstituted with one or more substituents selected from C₁₋₆alkyl,hydroxy, halo, cyano, C₁₋₆alkyloxycarbonyl;R² is aryl, C₃₋₇cycloalkyl or C₁₋₁₂alkyl wherein C₁₋₁₂alkyl mayoptionally be substituted with 1 or more substituents selected fromhydroxy, aryl, aryloxy, substituted or unsubstituted C₁₋₁₄heterocycle,hydroxycarbonyl, hydroxyC₁₋₆alkyloxy, or arylC₁₋₆alkylthio;R³ is aryl or a substituted or unsubstituted C₁₋₁₄heterocycle selectedfrom triazole, thiophene, quinoline, benzothiazole, quinoxaline,imidazole, benzimidazole, pyridine, pyrimidine and triazine;R⁴ is hydrogen.

A particular group of compounds are those compounds of formula (I)wherein L¹ is R¹—Y— with R¹ is hydrogen, phenyl, pyridinyl, phenylsubstituted with one or more substituents selected from halo, nitro,cyano, C₁₋₁₂alkyl, and C₁₋₁₂alkyloxy or pyridinyl substituted with oneor more substituents selected from C₁₋₆alkyl and cyano and wherein Y isC₁₋₄alkanediyl; L² is R¹—Y— with R¹ is hydrogen or cyano and wherein Yis C₁₋₄alkanediyl or a direct bond; ═Z¹—Z²═Z³— is a radical of formula(a-1); R² is aryl, C₁₋₁₂alkyl or C₁₋₁₂alkyl substituted with one or moresubstituents selected from aryl, and a substituted or unsubstitutedC₁₋₁₄heterocycle; R³ is aryl, a substituted or unsubstitutedC₁₋₁₄heterocycle selected from quinoline, quinoxaline, benzofuran,furan, dihydrobenzofuran, benzopyran, pyridine, benzothiophene,pyrrolidine, indene, benzodioxolane and thiophene, or a C₂₋₄alkenediylsubstituted with one or more substituents selected from naphthyl, phenyland phenyl substituted with one or more substituents selected from halo,cyano, nitro, substituted or unsubstituted phenyl, phenyloxy,trifluoromethyl, methoxy, thienyl, trifluoromethyloxy, morpholinyl andC₁₋₁₂alkyl; R⁴ is hydrogen.

Particular compounds are those compounds of formula (I) wherein L¹ issubstituted or unsubstituted benzyl, more in particular, p-cyano-benzyland L² is hydrogen.

Other particular compounds are those compounds of formula (I) wherein atleast one of the substituents R² and —X—R³ is p-phenoxy-phenyl orp-(phenylcarbonyl)-phenyl.

Also particular compounds are those compounds of formula (I) wherein—X—R³ is arylsulfonyl.

Further particular compounds are those compounds of formula (I) whereinR³ is C₂₋₄alkenediyl substituted with a substituted or unsubstitutedC₁₋₁₄heterocycle or wherein R³ is piperidinyl substituted witharylsulfonyl.

Also particular compounds are those compounds of formula (I) wherein—NR⁵R⁶ is arylamino.

Yet another particular group of compounds are those compounds of formula(I) wherein R² is C₁₋₁₂alkyl substituted with aryl.

A group of particularly interesting compounds of formula (I) are

a prodrug, N-oxide, addition salt, quaternary amine or stereochemicallyisomeric form thereof.

The most preferred compounds of formula (I) are

a prodrug, N-oxide, addition salt, quaternary amine or stereochemicallyisomeric form thereof.

The compounds of formula (I) can conveniently be prepared using solidphase synthesis techniques. In general, solid phase synthesis involvesreacting an intermediate in a synthesis with a polymer support. Thispolymer supported intermediate can then be carried on through a numberof synthetic steps. After each step, impurities are removed by filteringthe resin and washing it numerous times with various solvents. At eachstep the resin can be split up to react with various intermediates inthe next step thus allowing for the synthesis of a large number ofcompounds. After the last step in the procedure the resin is treatedwith a reagent or process to cleave the resin from the sample. Moredetailed explanation of the techniques used in solid phase chemistry aredescribed in for example “The Combinatorial Index” (B. Bunin, AcademicPress) and Novabiochem's 1999 Catalogue & Peptide Synthesis Handbook(Novabiochem AG, Switzerland) both incorporated herein by reference.

Along with the identification of the appropriate solvent, concentrationand temperature, the selection of solid support may influence the courseof the reaction. The compounds of the present invention were allprepared using 2-chlorotrityl chloride resin (Novabiochem AG,Switzerland). Hereinafter, said resin will be depicted as

The compounds of the present invention wherein R⁴ is hydrogen and═Z¹—Z²═Z³ is a radical of formula (a-1), said compounds beingrepresented by formula (I-a-1-a) can be prepared according to thefollowing general reaction scheme A.

Step 1: The 2-chlorotrityl chloride resin is reacted with1(H)-1,2,4-triazole-3-carboxaldehyde in a suitable solvent such as, forexample, N,N-dimethylformamide, 1,2-dichloroethane,N-ethyl-N-(1-methylethyl)-2-propanamine, dimethylacetamide,triethylamine, dichloromethane or a mixture thereof. Heating, stirringand the use of an inert atmosphere such as a nitrogen atmosphere mayenhance the reaction. After reaction, the resulting resin A-1 may bewashed, rinsed and dried using conventional techniques. For instance,the resin A-1 may be washed with N,N-dimethylformamide,dimethylacetamide, methanol, tetrahydrofuran or a mixture thereof,rinsed with CH₂Cl₂ and dried in vacuo.

Step 2: The resin A-1 is reacted with an amine of formula (III) in asuitable solvent such as, for example, 1,2-dichloroethane ordichloromethane, in the presence of an acid such as, for example, aceticacid or formic acid and in the presence of a reducing agent such as, forexample, sodium triacetoxyborohydride or sodium cyanoborohydride.Heating, stirring and/or sonification and the use of an inert atmospheresuch as a nitrogen atmosphere may enhance the reaction. After reaction,the resulting resin A-2 may be washed, rinsed and dried usingconventional techniques.

Step 3: Resin A-2 is reacted with an intermediate of formula (IV)wherein W¹ may be a leaving group and X may be a carbonyl group, asulfonyl group, a direct bond or in case R³ is to be connected to thenitrogen atom via a methylene group (ie. X is a methylene in resin A-3),W¹ may also be a formyl moiety. Suitable leaving groups are for instancea halogen, a hydroxy group, trifluoromethanesulfonate, methoxy,methylthio. In case W¹ is a formyl group, resin A-2 may be reductivelyN-alkylated according to the procedure described in step 2. In case W¹is a leaving group, the reaction may be performed in a suitable solventsuch as for example, dioxane, 1,2-dichloroethane, dichloromethane,tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide convenientlyin the presence of an appropriate base such as, for example, sodiumtert-butoxide, triethylamine, cesium carbonate,N-ethyl-N-(1-methylethyl)-2-propanamine, and also conveniently in thepresence of other reagents like coupling agents, reducing agents,Pd-ligands, catalysts such as, for example,tris(dibenzylideneacetone)dipalladium (0),[1,1′-binaphthalene]-2,2′-diylbis [diphenyl]-phosphine,1-[bis(dimethylamino)methylene]-hexafluorophosphate(1-)-1H-benzotriazolium,3-oxide, β-methyl-α,α-diphenyl-1-piperidineethanol, tributylphosphine,palladium (II) acetate, tri-o-tolylphosphine,(1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate(1-)-phosphorus(1+),1-[bis(dimethylamino)-methylene]-hexafluorophosphate(1-)-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide, 1-hydroxy-7-azabenzotriazole, diisopropylcarbodiimide. In caseX in resin A-3 is an amide or thioamide moiety, W1 may be a carbonyl orthiocarbonyl whereby X is a nitrogen atom connected to W with a doublebond (ie. W1-X is an isocyanate or isothiocyanate). Heating, stirringand/or sonification and the use of an inert atmosphere such as anitrogen atmosphere may enhance the reaction. After reaction, theresulting resin A-3 may be washed, rinsed and dried using conventionaltechniques.

Step 4: Resin A-3 is reacted with an intermediate of formula (V) whereinW² is a suitable leaving group such as, for example, hydroxy, halogen,trifluoromethanesulfonate. The reaction may be performed in a suitablesolvent such as, for example, CH₂Cl₂, 1,2-dichloroethane, convenientlyin the presence of other reagents like base, sulfonating agent, catalystsuch as, for example, N-ethyl-N-(1-methylethyl)-2-propanamine,trifluoroacetic acid anhydride. It may be necessary to cool the reactiontemperature to for example −78° C. Stirring and/or sonification and theuse of an inert atmosphere such as a nitrogen atmosphere may enhance thereaction. After reaction, the resin A-4 may be washed with a suitablesolvent such as methylene chloride, 1,2-dichloroethane etc. and driedusing conventional techniques.

Step 5: The resin in Resin A-4 was cleaved using art-known cleavingtechniques such as, for example, using a mixture of trifluoroacetic acidand CH₂Cl₂.

The compounds of the present invention wherein R⁴ is hydrogen and═Z¹—Z²═Z³ is a radical of formula (a-2), said compounds beingrepresented by formula (I-a-2-a) can be prepared according to thefollowing general reaction scheme B.

The reaction procedures of the different steps in scheme B are analogousto the reaction steps described for scheme A.

The compounds of the present invention wherein R⁴ is hydrogen and═Z¹—Z²═Z³— is a radical of formula (a-3), said compounds beingrepresented by formula (I-a-3-a) can be prepared according to thefollowing general reaction scheme C.

The reaction procedures of the different steps in scheme C are analogousto the reaction steps described for scheme A.

The compounds of the present invention wherein R⁴ is aryl,C₃₋₇cycloalkyl or C₁₋₆alkyl, said subgroup of R⁴ being represented byR^(4′), and ═Z¹—Z²═Z³— is a radical of formula (a-1), said compoundsbeing represented by formula (I-a-1-b) can be prepared according to thefollowing general reaction scheme D.

Step 1: This step is analogous to step 1 in scheme A.

Step 2: The resin D-1 is reacted with a Grignard reagent of formula (VI)in a suitable solvent such as, for example, tetrahydrofuran anddiethylether. Stirring and the use of an inert atmosphere such as anitrogen atmosphere may enhance the reaction. After reaction, theresulting resin D-2 may be washed, rinsed and dried using conventionaltechniques.

Step 3: The resin D-2 is reacted with an appropriate oxidizing reagentsuch as, for example, 2-iodoxybenzoic acid, Dess-Martin 12-I-5preiodinane reagent,1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one, in asuitable solvent such as, for example, dimethylsulfoxide and methylenechloride. Stirring and the use of an inert atmosphere such as a nitrogenatmosphere may enhance the reaction. However, caution should be usedwhen using potentially explosive hypervalent iodine compounds such asthe ones mentioned above. After reaction, the resulting resin D-3 may bewashed, rinsed and dried using conventional techniques.

Subsequent steps: The subsequent steps were performed analogous to steps2, 3, 4 & 5 in scheme A.

The compounds of the present invention wherein R⁴ is limited to thesubgroup R^(4′) and ═Z¹—Z²═Z³— is a radical of formula (a-2), saidcompounds being represented by formula (I-a-2-b) can be preparedanalogous to the general reaction scheme E but replacing of1H-1,2,4-triazole-3-carboxaldehyde by the triazole used in scheme B.

The compounds of the present invention wherein R⁴ is limited to thesubgroup R^(4′) and ═Z¹—Z²═Z³— is a radical of formula (a-3), saidcompounds being represented by formula (I-a-3-b) can be preparedanalogous to the general reaction scheme E but replacing of1H-1,2,4-triazole-3-carboxaldehyde by the triazole used in scheme B.

The compounds of the present invention wherein R⁴ is substitutedC₁₋₆alkyl, said subgroup of R⁴ being represented by R^(4″), and═Z¹—Z²═Z³— is a radical of formula (a-1), said compounds beingrepresented by formula (I-a-1-c) can be prepared according to thefollowing general reaction scheme E.

Step 1: This step is analogous to step 1 in scheme A.

Step 2: The resin E-1 is reacted with a Wittig reagent of formula (VII)in a suitable solvent such as, for example, tetrahydrofuran, dioxane,ether and 1,2-dimethoxyethane. Stirring and the use of an inertatmosphere such as a nitrogen atmosphere may enhance the reaction. Afterreaction, the resulting resin E-2 may be washed, rinsed and dried usingconventional techniques.

Step 3: The resin E-2 is reacted with an intermediate of formula (III)in the presence of a base such as, for example, n-butyllithium,potassium tert-butoxide, sodium hydride, potassium hydride, and in asuitable solvent such as, for example, tetrahydrofuran, dioxane and1,2-dimethoxy-ethane. Stirring and the use of an inert atmosphere suchas a nitrogen atmosphere may enhance the reaction. After reaction, theresulting resin E-3 may be washed, rinsed and dried using conventionaltechniques.

Subsequent steps: The subsequent steps were performed analogous to steps3, 4 & 5 in scheme A.

The compounds of the present invention wherein R⁴ is limited to thesubgroup R^(4″) and ═Z¹—Z²═Z³— is a radical of formula (a-2), saidcompounds being represented by formula (I-a-2-c) can be preparedanalogous to the general reaction scheme E but replacing of1H-1,2,4-triazole-3-carboxaldehyde by the triazole used in scheme B.

The compounds of the present invention wherein R⁴ is limited to thesubgroup R^(4″) and ═Z¹—Z²═Z³— is a radical of formula (a-3), saidcompounds being represented by formula (I-a-3-c) can be preparedanalogous to the general reaction scheme E but replacing of1H-1,2,4-triazole-3-carboxaldehyde by the triazole used in scheme C.

The compound of the present invention represented by formula (I-a-1-f)wherein R¹⁰ is a cycloalkyl, methylenecycloalkyl, aryl or aC₁₋₁₄heterocycle wherein said C₁₋₁₄hereocycle preferably containsnitrogen, optionally substituted with a protecting group, as heteroatom;and ═Z¹—Z²═Z³— is a radical of formula (a-1), said compounds can beprepared according to the following reaction scheme H.

Except for steps 4 & 5, all steps in the above scheme H are conducted ina similar manner as described for equivalent intermediates in Scheme A.

Step 4: The resin H-3 is treated with a deprotecting reagent as may bewell known in art such as cesium fluoride, tetrabutylammonium fluoride,piperidine etc. After reaction, the resulting resin H-4 may be washed,rinsed and dried using conventional techniques.

Step 5: The resin H-4 is reacted with a reagent of formula V, whereinreagent V is defined in the same way as reagent IV in Scheme A. Thereaction procedure is also similar as step 3 in general reaction SchemeA.

Variations to the above mentioned schemes A, B, C, D, E and H arepossible. For instance, it may be convenient to build the chemicalgroups defined in R² and R³ in different steps. The synthesis schemes Fand G below exemplify possible methods for such.

In the above scheme for example, reagent W¹—X—R³ is the same as reagentIV in Scheme A with the stipulation that R³ be an aryl or heteroarylgroup additionally substituted with a halogen. Reagent V may be an arylboronic acid {Ar—B(OH)₂}, a terminal acetylene, an olefin, a secondaryamine, a phenol or other hydroxy containing compound. Such reaction isconducted in the presence of a Pd-ligand and/or organometallic catalystssuch as tris(dibenzylideneacetone)dipalladium (0),tetrakis(triphenylphosphine) palladium (0),[1,1′-binaphthalene]-2,2′-diylbis[diphenyl]-phosphine,bis(triphenylphosphine)palladium dichloride, dichloro biscyanophenylpalladium (0), tri-tertbutylphosphine, copper (I) iodide, copper (II)chloride, Palladium (II) acetate, tri-o-tolylphosphine,1,4-bis(diphenylphosphino)butane (dppb),dichlorobis(triphenylphosphine)palladium etc. Such reactions are welldescribed in literature and are frequently referred to as Suzuki,Sonogashira, Buchwald or Heck reactions. Reviews on such reactions areavailable eg. Palladium catalysis in the synthesis of medicinal agents.Larsen, Robert D. Curr. Opin. Drug Discovery Dev. (1999), 2(6), 651-667.A comprehensive review of the applications of transition metal-catalyzedreactions to solid phase synthesis. Kingsbury, Celia L.; Mehrman, StevenJ.; Takacs, James M. Curr. Org. Chem. (1999), 3(5), 497-555. Thesereactions may be conducted in a suitable solvent such as toluene,dioxane, dimethoxyethane etc. In the structure I-a-1-D, the group R¹¹ istherefore an aryl, heteroaryl, aminocycloalkyl, amino subst alkyl, arylacetylene, carbonylaryl, etc. All steps in above Scheme F except step 4are conducted in a similar manner as described for equivalentintermediates in Scheme A. Steps 3a and 3b in example A5 furtherexemplify this synthesis route.

Further variations to the general reaction schemes A, B, C, D, E and Hcan be achieved following reaction scheme G.

The R³ group in reagent IV above is similar to that described for SchemeA with the stipulation that it must contain a group that can bedisplaced by a nucleophile. Example groups include a halomethylene(CH₂—C₁ or CH₂—Br) or ortho-nitrofluoro phenyl moiety. The descriptionsfor resin F-3 can therefore be X═CO, SO₂; R³═CH₂C₁, C₆H₄CH₂C₁,C₆H₄—CH₂Br, C₆H₄(NO₂)(ortho-F) etc. All steps in above scheme G exceptstep 4, is conducted in a similar manner as described for equivalentintermediates in scheme A. The procedure for step 4 involves reactionwith a nucleophile such as a secondary or primary amine additionallysubstituted with an alkyl, heteroalkyl, aryl, heteroaryl moiety, or asimilarly substituted thiol or a hydroxy bearing agent. The nucleophilemay also be a heterocycle containing a nucleophilic nitrogen atom suchas a substituted imidazole, triazole, indole, benzimidazole etc. Thedescriptions of groups for resin F-4, F-5 and structure I-a-1-e aretherefore R¹² is Alkyl, subst. alkyl, Aryl, heteroaryl, cycloalkyl,cycloaryl, etc. and Z is NH, N, O, S.

Other variations to R² and R³ group modifications are also possible. Forexample, The R³ group may be a substituted benzimidazole or indolegroup, when ortho-fluoro or ortho-iodo nitro benzene groups are attachedto the nitrogen atom in resin A-2 (Scheme A) employing proceduressimilar to those described for step 3 in Scheme A. Such ortho-fluoro orortho-iodo benzene is then further modified to substituted indole orbenzimidazole groups employing solid phase synthesis methods wellestablished in art. It is also readily possible to effect similar typesof modifications to the R² group as those discussed for R³ group above.In all solid phase synthesis techniques, a method to facilitate rapidparallel synthesis of compound libraries such as some well described inart was employed.

Solution phase synthesis methods employing traditional procedures andschemes well established in art may also be utilized for synthesis ofall target compounds described. Such methods were most useful for scaleup of intermediates and in synthesis of compounds wherein ═Z¹—Z²═Z³—represents a radical of formula (a-1) and L¹ and L² in structure I-a-1-g(Scheme J) are R¹—Y— whereby Y is C₁₋₄alkanediyl for L¹, and whereby Yis C₁₋₄alkanediyl or a direct bond for L². This synthesis scheme shownbelow is not limited to only these compounds however and can be readilyutilized by one practiced in the art for a diversity of structuresotherwise inaccessible by solid phase synthesis. Example procedures forvarious steps employed in Scheme J can be found in De Lombaert, S. De etal. J. Med. Chem. 2000, 43, 488; Owens, A. P. et. al. Bioorg. Med. Chem.Lett. 1998, 8, 51; Baldwin, J. J. et al. J. Med. Chem. 1975, 18, 895etc.

Step 1: The amine which is commercially available or can be made usingconventional techniques, is reacted with an α-haloacyl halide such asfor example, chloroacyl chloride or bromoacyl bromide in the presence ofa suitable base such as, for example, N,N-diisopropylethylamine and asuitable solvent such as, for example, toluene to give intermediate J-1after a brief work up.

Step 2: Intermediate J-1 is activated with an activating agent such asfor example trifluoromethane sulfonic anhydride or phosphoruspentachloride in a suitable solvent such as, for example, acetonitrileand subsequently treated with an acyl hydrazide of formula II, wherebythe L² group may be an alkyl, substituted alkyl, a substituted orunsubstituted C₁₋₁₄heterocycle, cyano or an aryl moiety.

Step 3: The intermediate J-2 was heated without isolation resulting inintermediate J-3, which was isolated after a work up and chromatographyconform to those well described in art.

Step 4: Reaction with an amine of formula III (as described in Scheme A)in the absence or presence of a suitable activating agent such as, forexample, potassium iodide in a suitable solvent such as, for example,acetonitrile produced intermediate J-4 after work up and isolation.

Step 5: This step was carried out in the same manner as described forstep 3 in Scheme A, except that work up and isolation proceduresconformed to those well described in art for solution phase synthesiswith or without the aid of scavenger resins and thereafter, orsimultaneously therewith, effecting one or more of the followingoptional conversions:

-   (i) when the compound of formula (I) is formed, converting it into    another compound of formula (I) having different values of L¹, L²,    R², R³, and R⁴ by treatment with an appropriate reagent and/or under    suitable conditions;-   (ii) removing any remaining protecting groups;-   (iii) when the compound of formula (I) is formed, converting into a    prodrug, N-oxide, addition salt, quaternary amine or    stereochemically isomeric form thereof;-   (iv) when a pharmaceutically acceptable derivative of a compound of    formula (I) is formed, converting the said derivative into a    compound of formula (I), or a different derivative thereof.

Example A7 further exemplify this synthesis route.

Variations to the above mentioned schemes A, B, C, D and E are possible.For instance, it may be convenient to build the chemical groups definedin R² and R³ in different steps. Steps 3a and 3b in example A5 exemplifythis synthesis route.

Another example of such variation is exemplified in example A6. There,the cleavage from the resin is performed prior to reacting the thusformed monosubstituted triazole derivative with an intermediate offormula (IV).

Said monosubstituted triazoles, generally depicted as follows

are interesting and useful intermediates in the preparation of thecompounds of formula (I). Some of said monosubstituted triazoles alsoshow interesting farnesyl transferase inhibiting activity.

The intermediates used in the above synthesis schemes are eithercommercially available or can be prepared according to generally knownsynthesis procedures.

The compounds of formula (I) containing a stereogenic center as preparedin the hereinabove described processes are generally racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I) may beconverted into the corresponding diastereomeric salt forms by reactionwith a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

Compounds of formula (I) may be converted into an ester by reaction withan appropriate esterifying agent, for example, an acid halide oranhydride. Where it is desired to isolate a compound of formula (I) asan acid addition salt, for example, a physiologically acceptable acidaddition salt, the salt may be formed by reacting the compound offormula (I) in the form of the free base with the appropriate acid. Thetwo reactants are preferably used in equivalent amounts and the reactionmay be carried out in a suitable solvent such as an alcohol, for exampleethanol, an ester, for example ethyl acetate, or an ether, for exampletetrahydrofuran. One salt of a compound of formula (I) may be convertedinto another salt using standard methods, for example where it isdesired to convert a salt of a compound of formula (I) with an acidwhich is not physiologically acceptable into a salt with aphysiologically acceptable acid. An ester or salt may be converted intothe parent compound, for example by hydrolysis.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereoisomeric forms thereof have valuablepharmacological properties in that they surprisingly have valuablefarnesyl protein transferase (FPTase) and/or geranylgeranyltransferaseinhibitory effects.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g. loss of contactinhibition). This includes the abnormal growth of: (1) tumor cells(tumors) expressing an activated ras oncogene; (2) tumor cells in whichthe ras protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of tumors in vivo by a direct effect on tumor cell growth butalso indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak.J. et al, Cancer Research, 55, 4575-4580, 1995). Hence,pharmacologically targeting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumors expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumors which may be inhibited, butare not limited to, lung cancer (e.g. adenocarcinoma), pancreaticcancers (e.g. pancreatic carcinoma such as, for example exocrinepancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, suchas, for example, colon adenocarcinoma and colon adenoma), hematopoietictumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-celllymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acutemyelogenous leukemia (AML)), thyroid follicular cancer, myelodysplasticsyndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas andrhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas,gliomas, benign tumor of the skin (e.g. keratoacanthomas), breastcarcinoma, kidney carcinoma, ovary carcinoma, bladder carcinoma andepidermal carcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes. With saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneuro-fibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention.

The compounds of present invention are particularly useful for thetreatment of proliferative diseases, both benign and malignant, whereinthe K-ras B isoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove mentioned conditions.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, to aidsolubility for example, may be included. Injectable solutions, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not cause a significantdeleterious effect to the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. It isespecially advantageous to formulate the aforementioned pharmaceuticalcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used in the specification andclaims herein refers to physically discrete units suitable as unitarydosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.01 mg/kg to 100mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of activeingredient per unit dosage form.

The present invention also relates to a combination of an antineoplasticagent and a compound of the present invention, i.e. a farnesyltransferase inhibitor, and thus relates also to a method of treatingcancer using said combination, which method comprises administering to amammal, either sequentially in any order or simultaneously, therapeuticeffective amounts of at least one antineoplastic agent and one compoundof the present invention. The present invention thus also relates to acombination of an antineoplastic agent and a compound of the presentinvention for use as a medicine.

Examples of an antineoplastic agent include, for instance,microtubule-stabilising agents such as paclitaxel, docetaxel, epothiloneA, epothilone B, desoxyepothilone A, desoxyepothilone B or derivativesthereof, microtubule-disruptor agents; alkylating agents;anti-metabolites; a fusel poison; epidophyllotoxin; an antineoplasticenzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinumcoordination complexes; biological response modifiers and growthinhibitors; hormonal and anti-hormonal therapeutic agents andhematopoietic growth factors.

Example classes of antineopastic agents include, for instance, theanthracycline family of drugs, vinca drugs, mitomycins, bleomycins,cytotoxic nucleosides, taxanes, epothilones, discodermolide, thepteridine family of drugs, diynenes and the podophyllotoxines.

Examples of particularly useful antineoplastic agents includedoxorubicin, caminomycin, daunorubicin, aminopterin, methotrexate,metopterin, dichloro-methotrexate, mitomycin C, porfiromycin,5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside,podophyllotoxin or podophyllotoxin derivatives such as etoposide,etoposide phosphate or teniposide, melphalan, vinblastine, vincristine,leurosidine, vindesine, leurosine, paclitaxel, estramustine, cisplatine,carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide,hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate,dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C,bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives,interferons and interleukins.

Said combination may also be used in conjunction with other methods oftreating cancers and/or tumors, including radiation therapy and surgery.Radiation therapy, including X-rays or gamma-rays which are deliveredfrom either an externally applied beam or by implantation of radioactivesources, may also be used in combination with a compound of the presentinvention alone to treat cancer. The compound of formula (I) may beadministered concurrently with the radiation therapy or may beadministered prior to the application of the radiation.

According to a further aspect of this invention the compounds of formula(I) or any subgroup thereof show antiviral properties. Viral infectionstreatable using the compounds and methods of the present inventioninclude those infections brought on by ortho- and paramyxoviruses and inparticular by human and bovine respiratory syncytial virus (RSV).

The in vitro antiviral activity against RSV of the present compounds wastested in a test as described in the experimental part of thedescription, and may also be demonstrated in a virus yield reductionassay. The in vivo antiviral activity against RSV of the presentcompounds may be demonstrated in a test model using cotton rats asdescribed in Wyde et al. (Antiviral Research (1998), 38, 31-42).

Due to their antiviral properties, particularly their anti-RSVproperties, the compounds of formula (I) or any subgroup thereof, theirprodrugs, N-oxides, addition salts, quaternary amines, metal complexesand stereochemically isomeric forms, are useful in the treatment ofindividuals experiencing a viral infection, particularly a RSVinfection, and for the prophylaxis of these infections. In general, thecompounds of the present invention may be useful in the treatment ofwarm-blooded animals infected with viruses, in particular therespiratory syncytial virus.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines. Said use as a medicine or method oftreatment comprises the systemic administration to viral infectedsubjects or to subjects susceptible to viral infections of an amounteffective to combat the conditions associated with the viral infection,in particular the RSV infection.

The following examples are provided for purposes of illustration.

EXPERIMENTAL PART A Preparation of the Compounds of Formula (I)Following Scheme A

Hereinafter, the following acronyms are used: DMF[N,N-dimethylformamide], DCE [1,2-dichloroethane], DCM[dichloromethane], DIEA [N-ethyl-N-(1-methylethyl)-2-propanamine]

Example A1

Preparation of

Step 1:

DMF (45.0 mL) and DIEA (15.0 mL, 0.0861 mole) were added to a hotsolution of 1H-1,2,4-triazole-3-carboxaldehyde (2.71 g, 0.0279 mole).The mixture was heated while shaking until homogeneous. The warmsolution was diluted with DCE (15.0 mL), and the solution was added tothe pre-swelled 2-chlorotrityl chloride resin (10.00 g, 0.010 mole). Thesolution was heated at 60° C. overnight with intermittent N₂ bubbling.The resulting resin was drained, then heated in DMF (45 mL) at 60° C.for 30 min. The warm DMF washing was repeated four times. The resin wasrinsed with DCM (4×) and methanol (4×) and dried in vacuo overnight.

Step 2:

A solution of the 4-bromo-benzeneethanamine (0.025 mole) in1,2-dichloroethane (99.0 mL) and acetic acid (1.00 mL) was added to thepre-swelled resin from step 1 (0.005 mole). The mixture was sonicatedfor 5 min at 23° C. then heated to 60° C. for 30 min with intermittentN₂ bubbling. Na(AcO)₃BH (5.299 g, 0.025 mole) was added. The mixture wassonicated for 5 min at 23° C. then heated to 60° C. for 30 min withintermittent N₂ bubbling. The heat source was removed, and the reactionwas allowed to bubble overnight at 23° C. Excess Na(AcO)₃BH was quenchedwith methanol. The resin was rinsed with DMF (4×) and methanol (4×),then dried in vacuo overnight.

Step 3:

The resin from step 2 (0.00113 mole) was weighed into a custom 200 mLsolid phase synthesis bottle and the 4-phenoxybenzaldehyde (0.00565mole) was added in a solution of 1% acetic acid-DCE (28.6 mL). Themixture was purged with N₂ and sonicated in a warm (60° C.) ultrasonicbath for 10 min. The mixture was then allowed to gently agitate under N₂for 16 hour. A pre-sonicated solution of NaBH(OAc)₃ (0.00565 mole) wasthen added and reaction vessel sonicated for 10 min at 60° C. and thenallowed to gently agitate under N₂ overnight. The resulting resin wasthen washed with methanol (2×), DMF (6×), methanol (4×), and DCM (6×).

Step 4:

A solution of the 4-(hydroxymethyl)-benzonitrile (0.00019 mole) and DIEA(0.00019 mole) in DCM (1 mL) was added to the resin from step 3(0.000093 mole). A solution of trifluoroacetic acid anhydride in DCM (1mL) was added to the mixture at −78° C. The reaction was agitated underN₂ for 30 min at −78° C., then at room temperature for 4 hr. Thesolution was removed through filtration. The reaction was repeated onthe resin. The solutions were combined, dried under N₂, and purified byHPLC.

Step 5:

95:5 Trifluoroacetic acid: DCM (5 mL) was added to the dried resin fromstep 4 (0.0001 mole). The resin was allowed to sit in the cleavagesolution for 2 hr. The resin was filtered off, and the solvent wasremoved from the resulting solution using a Savant speedvac. Theresulting residue was combined with the solution obtained from step 4and purified by reverse phase HPLC utilizing a gradient of acetonitrilewith 0.1% trifluoroacetic acid to water with 0.1% trifluoroacetic acid.The pure fractions from HPLC were combined, frozen, and lyophilizedovernight.

Example A2

Preparation of

Step 1 & 2: Analogous to Step 1 & 2 of Example A1Step 3:

The resin from step 2 (0.000075 mole) was swelled in DCM (10 mL) andthen drained. A solution of DIEA (0.87 mL, 0.0025 mole) in 1 M DCE wasadded, followed by a solution of the sulfonyl chloride (0.0025 mole) in0.5 M DCE. The resulting suspension was shaken with gyrating motionunder intermittent N₂ purge for 12 hours. The solvent was then removed,and the resin was washed 6 times with DCM, twice DMF, 4 times with DCM,and finally 6 times with methanol. The resulting resin was then dried invacuum.

Step 4 & 5: Analogous to Step 4 & 5 of Example A1.

Example A3

Preparation of

Step 1 & 2: Analogous to Step 1 & 2 of Example A1Step 3:

A solution of the 2-quinolinecarboxylic acid (0.00025 mole),1-[bis(dimethylamino)methylene]-hexafluorophosphate(1-)-1H-benzotriazolium3-oxide (0.00025 mole) and DIEA (0.0005 mole) in DMF (2 mL) was added tothe resin from step 2 (0.000091 mole). The reaction mixture was agitatedunder N₂ overnight at room temperature. The solvent was drained and theresulting resin was washed extensively with DMF, methanol, and DCM. Theresulting resin was dried under N₂

Step 4 & 5: Analogous to step 4 & 5 of example A1.

Example A4

Preparation of

Step 1 & 2: Analogous to Step 1 & 2 of Example A1Step 3:

A solution of 2-chloro-5-ethyl-pyrimidine (0.00157 mole) in dioxane andDIEA (0.00189 mole) were added to the resin from step 2 (0.00105 mole).The reaction mixture was heated at 85° C. for 2 days. The resultingresin was washed with DMF, methanol, and DCM, then dried under N₂.

Step 4 & 5: Analogous to Step 4 & 5 of Example A1

Example A5

Preparation of

Step 1 & 2: Analogous to Step 1 & 2 of Example A1Step 3a:

This step was accomplished analogous to step 3 in example A2.

Step 3b:

Dimethyl ether (1.6 mL) was added to the resin from step 3a (0.0001mole). The resulting suspension was degassed by bubbling Ar for severalminutes. Pd[P(C₆H₅)₃]₄ (0.0004 mole) was added, and the mixture wasagitated for 5 minutes. The (3-chloro-4-fluorophenyl)-boronic acid(0.0004 mole) and sodium carbonate (0.0005 mole) were added. The mixturewas then refluxed for 14 hours under gentle Ar purging. The mixture wascooled to room temperature, diluted with 25% ammonium acetate, andstirred for 5 minutes and drained. The resulting resin was successivelywashed with 2 mL each of 1:1 dimethyl ether: H₂O, 0.2N HCl, H₂O,dimethyl ether, DCM, and methanol. The resin was dried in a high vacuum.

Step 4 & 5: Analogous to Step 4 & 5 of Example A1.

Example A6

Preparation of

Step 1 & 2: Analogous to Step 1 & 2 of Example A1Step 3: Analogous to Step 3 of Example A2.Step 4:

The cleavage was performed analogous to step 5 in example A1.

Step 5:

Sodium hydride (0.00069 mole) was added to a solution of the triazoleresulting from step 4 in dimethylsulfoxide (2 mL). After 10 minutes 25°C., 1-(bromomethyl)-4-chlorobenzene (0.00104 mole) was added, and theresulting solution was left overnight at 25° C. The pre-swelledscavenger resin to remove excess, 1-(bromomethyl)-4-chlorobenzene wasadded. The resin was filtered off, and the resulting rinses werecombined with the reaction solution. The dimethylsulfoxide solution wasdiluted tenfold with water, and passed through a solid phase extractioncolumn, then rinsed with water. The compound 1 was eluted withacetonitrile, purified by preparatory HPLC, frozen, and lyophilized.

Example A7

Preparation of

Step 1:

To a solution of 4-cyanobenzylamine (13.21 g, 0.1 mole) andN,N-diisopropylethylamine (12.93 g, 0.11 mole) in toluene (75 mL) underargon at 0° C., chloroacetyl chloride (11.30 g, 0.1 mole) was addeddropwise. After the addition was complete, the reaction mixture wasstirred for 45 min at room temperature. Ethyl acetate (250 mL) wasadded, followed by a solution of sat NH₄Cl (250 mL). The organic layerwas separated, and the aqueous layer was extracted with ethyl acetate(250 mL). The combined organic layers were dried over MgSO₄ and treatedwith charcoal. The drying agent was removed by filtration, and thefiltrate was concentrated to a volume of ˜50 mL. A solid precipitatedwhich was removed by filtration. The solid was dried under vacuum toyield 14.25 g (68.3%) of 4-cyanobenzyl-5-methyl-1,2,4-triazole.

Step 2:

Triflic anhydride (1.66 g; 5.9 mmole) was added dropwise to a solutionof 4-cyanobenzyl-5-methyl-1,2,4-triazole (1.04 g; 5 mmole) inacetonitrile (25 mL) at 0° C. under Ar. The cooling bath was removed,and acetic hydrazide (0.96 g; 13 mmole) was added. The reaction wasstirred at RT for 20 hr. The reaction was heated at 100° C. for 3 hr,then allowed to cool to RT. Water (5 mL) was added, and the reaction wasevaporated. The residue was treated with sat K₂CO₃ (5 mL), and extractedwith ethyl acetate (2×30 mL). The organic phase was dried over Na₂SO₄,filtered, and evaporated. The residue was purified by reverse phase HPLCto yield 0.080 g (6.5%) of desired 3-chloromethyl-4-cyanobenzyl-5 methyltriazole.

Step 3:

3-Chloromethyl-4-cyanobenzyl-5 methyl triazole (0.080 g; 0.32 mmole) and2,4-difluorobenzylamine (0.254 g; 1.77 mmole) were combined inacetonitrile (10 mL), and stirred under argon for 7 days at roomtemperature. The formed solid was removed by filtration, and thefiltrate was concentrated to dryness at 35° C. under a nitrogen flow.After reverse phase HPLC purification, the compound was readsorbed ontothe column and eluted with a dilute HCl solution and lyophilized toyield 0.033 g (26.2%) of desired secondary amine.

Step 4:

Secondary amine (33 mg; 0.085 mmole), quinaldic acid (19 mg; 0.11mmole), 1-hydroxybenzotriazole (HOBt; 18 mg; 0.13 mmole),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 25 mg;0.13 mmole), and N,N-diisopropylethylamine (32 mg; 0.25 mmole) werecombined in anhydrous tetrahydrofuran (10 mL). The reaction was stirredat room temperature for 20 hr. The solvent was removed under a nitrogenflow, and the residue was purified by reverse phase HPLC to yield 20 mg(46.5%) desired triazole.

Example A8

Preparation of

Step 1 & 2: Analogous to Step 1 & 2 of Example A1Step 3:

A solution of 4-Bromodiphenyl ether (0.0015 mole) in dioxane (1 mL) wasadded to the resin from step 2 (0.0001 mole) under nitrogen. A solutionof Pd₂ dba₃ (0.00002 mole), BINAP (0.00004 mole) and sodiumtert-butoxide (0.0018 mole) in dioxane (2 mL) was added to thesuspension resin. The reaction mixture was agitated under N₂ overnightat 80° C. The solvent was drained and the resulting resin was washedwith H₂O, DMF, DCM, methanol and DCM. The resulting resin was driedunder N₂.

Step 4 & 5: Analogous to Step 4 & 5 of Example A1

Example A9

Preparation of

Step 1 & 2: Analogous to Step 1 & 2 of Example A1Step 3a:

This step was accomplished analogous to step 3 in example A3

Step 3b:

This step was accomplished analogous to step 3b in example A5

Step 4 & 5: Analogous to Step 4 & 5 of Example A1

The following compounds were prepared analogous to example A1: 3, 7 to13, 23 to 64, 88 to 140, 150 to 158, 168 to 177, 179 to 185 & 217.

The following compounds were prepared analogous to example A2: 4 to 6 &14 to 22

The following compounds were prepared analogous to example A3: 141 to149, 218 to 220, 222, 223, 225, 226, 229, 231 to 233, 236, 237, 240,241, 243 to 254, 256, 258, 262 to 271, 273, 275 to 277, 280, 282, 284 to286, 289 to 291, 293 to 295, 297 to 307, 310, 314 & 315.

The following compounds were prepared analogous to example A4: 159 to167 & 178.

The following compounds were prepared analogous to example A5: 186 to216.

The following compounds were prepared analogous to example A6: 1 & 2.

The following compounds were prepared analogous to example A7: 311 to313

The following compounds were prepared analogous to example A8: 65 to 87

The following compounds were prepared analogous to example A9: 221, 224,227, 230, 235, 239, 242, 259, 260, 272, 274, 278, 281, 238, 287, 288,292, 296 & 308.

All of the above exemplified are depicted herein below.

By way of illustration, the following table lists some physical data ofthe above exemplified compounds. The column “Rt LC” shows the retentiontime in minutes of the compound after liquid chromatography on a SupelcoAZB Plus 4.6 mm 33 mm, 3 micron column using the method: 0.1%trifluoroacetic acid in CH₃CN to 0.1% trifluoroacetic acid in water, 10min.

Comp Rt LC Synthesis No (min) Purity MH⁺ scheme 1 6.23 98.3 467 3 5.27100 578/580 4 6.02 96.8 566 62 10.03 100 526 85 5.32 97.82 506 141 9.56100 551/553 164 5.33 100 502/504 192 10.66 99.3 654 218 5.11 100.0529.38 A 219 5.22 100.0 570.27 A 220 5.00 100.0 582.48 A 221 10.72 98.3603.47 F 222 5.50 100.0 580.31 A 223 5.61 100.0 557.49 A 224 10.40 99.2587.02 F 225 9.84 94.3 498.55 A 226 10.27 100.0 595.52 A 227 10.24 98.5588.55 F 228 10.67 94.9 641.13 F 229 4.67 100.0 513.32 A 230 10.48 100.0760.30 F 231 9.78 93.7 538.49 A 232 8.77 100.0 459.52 A 233 5.49 92.1529.46 A 234 9.97 98.0 508.54 A 235 10.43 93.5 602.58 F 236 4.72 96.3503.58 A 237 5.45 100.0 571.45 A 238 10.03 100.0 526.53 A 239 9.57 100.0526.58 F 240 9.83 100.0 567.39 A 241 9.76 100.0 549.40 A 242 10.05 100.0534.58 F 243 9.30 95.3 523.36 A 244 4.96 100.0 545.41 A 245 9.95 89.5556.48 A 246 9.18 97.8 478.90 A 247 4.23 96.5 449.49 A 248 8.08 100.0530.60 A 249 9.52 98.8 504.94 A 250 10.12 91.7 539.38 A 251 5.45 100.0541.43 A 252 8758.00 98.9 512.49 A 253 9.07 100.0 458.48 A 254 9.54100.0 484.52 A 255 4.96 100.0 604.51 A 256 9.33 100.0 537.59 A 257 9.7293.2 528.51 A 258 9.48 100.0 496.53 A 259 10.12 100.0 588.55 F 260 10.29100.0 548.61 F 261 9.84 92.4 677.81 H 262 9.29 97.4 472.51 A 263 9.13100.0 518.55 A 264 9.59 96.1 508.00 A 265 5.56 97.5 551.46 A 266 9.9893.1 546.59 A 267 9.31 100.0 500.52 A 268 4.97 97.6 514.50 A 269 9.56100.0 552.45 A 270 5.17 98.7 500.54 A 271 9.71 97.1 572.08 A 272 9.9092.4 562.95 F 273 5.08 100.0 515.49 A 274 9.54 100.0 528.51 F 275 9.41100.0 493.97 A 276 9.21 98.6 491.54 A 277 9.61 100.0 537.38 A 278 9.28100.0 527.57 F 279 4.62 100.0 479.89 A 280 9.53 100.0 543.52 A 281 9.85100.0 578.51 F 282 9.39 100.0 484.52 A 283 10.66 98.4 589.44 F 284 9.77100.0 528.41 A 285 4.70 100.0 524.35 A 286 5.45 100.0 528.41 A 287 9.74100.0 524.54 F 288 9.88 99.1 540.61 F 289 9.33 100.0 498.50 A 290 5.10100.0 545.52 A 291 9.35 100.0 565.39 A 292 9.96 100.0 578.51 F 293 9.9288.6 562.90 A 294 9.18 89.2 493.97 A 295 4.54 100.0 496.49 A 296 10.3997.0 579.41 F 297 9.06 100.0 477.51 A 298 4.55 97.7 525.53 A 299 4.96100.0 484.48 A 300 8.97 100.0 495.50 A 301 4.14 91.0 512.49 A 302 9.6896.0 527.52 A 303 8.81 98.0 495.50 A 304 9.58 93.1 538.43 A 305 9.30100.0 495.50 A 306 8.94 93.4 477.51 A 307 9.05 100.0 495.50 A 308 10.8498.7 603.47 F 309 9.57 100.0 537.38 A 310 9.04 100.0 504.52 A 311 8.8697.0 509.53 A 312 9.10 100.0 523.00 J 313 9.11 100.0 495.00 J

B. Pharmacological Example Example B1 “In Vitro Assay for Inhibition ofFarnesyl Protein Transferase”

An in vitro assay for inhibition of farnesyl transferase was performedessentially as described in WO 98/40383, pages 33-34.

The compound Nos. 4, 10, 11, 12, 13, 16, 23, 24, 25, 26, 29, 45, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 68, 69, 75,79, 80, 83, 85, 108, 126, 129, 140, 141, 145, 146, 149, 153, 154, 156,159, 160, 161, 162, 163, 170, 176, 180 and 182 had an inhibition ofFPTase activity of at least 5% at a test dose of 10⁻⁵ M or lower.

The compound Nos. 218 to 315 had an inhibition of FPTase activity of atleast 10% at a test dose of 10⁻⁷ M.

Example B2 “In Vitro Screening for Activity Against RespiratorySyncytial Virus”

The percent protection against cytopathology caused by viruses(antiviral activity or IC₅₀) achieved by tested compounds and theircytotoxicity (CC₅₀) were both calculated from dose-response curves. Theselectivity of the antiviral effect is represented by the selectivityindex (SI), calculated by dividing the CC₅₀ (cytotoxic dose for 50% ofthe cells) by the IC₅₀ (antiviral activity for 50% of the cells).

Automated tetrazolium-based calorimetric assays were used fordetermination of IC₅₀ and CC₅₀ of test compounds. Flat-bottom, 96-wellplastic microtiter trays were filled with 180 μl of Eagle's BasalMedium, supplemented with 5% FCS (0% for FLU) and 20 mM Hepes buffer.Subsequently, stock solutions (7.8×final test concentration) ofcompounds were added in 45 μl volumes to a series of triplicate wells soas to allow simultaneous evaluation of their effects on virus- andmock-infected cells. Five five-fold dilutions were made directly in themicrotiter trays using a robot system. Untreated virus controls, andHeLa cell controls were included in each test. Approximately 100 TCID₅₀of Respiratory Syncytial Virus was added to two of the three rows in avolume of 50 μl. The same volume of medium was added to the third row tomeasure the cytotoxicity of the compounds at the same concentrations asthose used to measure the antiviral activity. After two hours ofincubation, a suspension (4×10⁵ cells/ml) of HeLa cells was added to allwells in a volume of 50 μl. The cultures were incubated at 37° C. in a5% CO₂ atmosphere. Seven days after infection the cytotoxicity and theantiviral activity was examined spectrophotometrically. To each well ofthe microtiter tray, 25 μl of a solution of MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) wasadded. The trays were further incubated at 37° C. for 2 hours, afterwhich the medium was removed from each cup. Solubilization of theformazan crystals was achieved by adding 100 μl 2-propanol. Completedissolution of the formazan crystals were obtained after the trays havebeen placed on a plate shaker for 10 min. Finally, the absorbances wereread in an eight-channel computer-controlled photometer (Multiskan MCC,Flow Laboratories) at two wavelengths (540 and 690 nm). The absorbancemeasured at 690 nm was automatically subtracted from the absorbance at540 nm, so as to eliminate the effects of non-specific absorption.

Particular IC₅₀, CC₅₀ and SI values are listed in the Table hereinbelow.

Co. No. IC₅₀ (μM) CC₅₀ (μM) SI 90 0.0259 7.59 1988 97 0.0800 7.10 322102 0.0824 7.08 793 46 0.0881 7.06 758 157 0.0931 7.03 272 114 0.11836.93 337 101 0.1279 6.89 196 92 0.1503 6.82 147 155 0.1600 6.80 99

1. A compound of formula

a prodrug, N-oxide, addition salt, quaternary amine or stereochemicallyisomeric form thereof, wherein L¹ and L² are R¹—Y— wherein each (R¹—Y)—substituent is defined independently of the other; Y is C₁₋₄alkanediyl,C₂₋₄alkenediyl, C₂₋₄alkynediyl, C(═O), or a direct bond; R¹ is hydrogen,cyano, aryl or a substituted or unsubstituted C₁₋₁₄heterocycle;═Z¹—Z²═Z³— represents a radical of formula═N—N═CH—  (a-1)═N—CH═N—  (a-2)═CH—N═N—  (a-3) X is SO₂, (CH₂)_(n) wherein n is 1 to 4, C(═O), C(═S),or a direct bond R² is aryl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl substitutedwith one or more substituents independently selected from hydroxy, aryl,aryloxy, a substituted or unsubstituted C₁₋₁₄heterocycle,C₃₋₇cycloalkyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl,hydroxyC₁₋₆alkyloxy, hydroxyC₁₋₆alkylthio and arylC₁₋₆alkylthio,C₁₋₁₂alkyl or C₁₋₁₂alkyl substituted with one or more substituentsindependently selected from hydroxy, aryl, aryloxy, a substituted orunsubstituted C₁₋₁₄heterocycle, C₃₋₇cycloalkyl, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkyloxy,hydroxyC₁₋₆alkylthio and arylC₁₋₆alkylthio; R³ is aryl, —NR⁵R⁶, asubstituted or unsubstituted C₁₋₁₄heterocycle, or C₂₋₄alkenediylsubstituted with a substituted or unsubstituted C₁₋₁₄heterocycle oraryl; R⁴ is hydrogen, aryl, C₃₋₇cycloalkyl, C₁₋₆alkyl or C₁₋₆alkylsubstituted with C₃₋₇cycloalkyl, hydroxycarbonyl, C₁₋₄alkyloxycarbonylor aryl; R⁵ and R⁶ are each independently selected from hydrogen, asubstituted or unsubstituted C₁₋₁₄heterocycle, aryl, C₁₋₁₂alkyl andC₁₋₁₂alkyl substituted with one or more substituents selected fromhydroxy, aryl, aryloxy or a substituted or unsubstitutedC₁₋₁₄heterocycle; R⁷ is substituted or unsubstituted phenyl, —NR⁸R⁹ or asubstituted or unsubstituted C₁₋₁₄heterocycle; R⁸ and R⁹ areindependently selected from hydrogen, substituted or unsubstitutedphenyl, C₃₋₆cycloalkyl, a substituted or unsubstituted C₁₋₁₄heterocycle,C₁₋₆alkyl and C₁₋₆alkyl substituted with one or more substituentsindependently selected from C₁₋₄alkyloxycarbonyl,hydroxycarbonyl,substituted or unsubstituted phenyl and a substituted or unsubstitutedC₁₋₁₄heterocycle; aryl, as a group or part of a group, is naphthyl orphenyl each of which may optionally be substituted with one or moresubstituents selected from trifluoromethyl, trifluoromethyloxy, halo,cyano, nitro, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, phenylC₁₋₆alkyl,phenylC₁₋₆alkyloxy, phenyloxy, phenylcarbonyl, hydroxycarbonyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, amino, mono- ordi(C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)amino wherein said C₁₋₄alkylis substituted with one or more substituted or unsubstituted phenyl,S(O)₂—R⁷, C₁₋₆alkylcarbonylamino, substituted or unsubstituted phenyl,and a substituted or unsubstituted C₁₋₁₄heterocycle.
 2. A compoundaccording to claim 1 wherein; a) Y is C₁₋₄alkanediyl, or a direct bond;or b) R¹ is hydrogen, cyano, aryl or a substituted or unsubstitutedC₁₋₁₄heterocycle; or c) ═Z¹—Z³═Z³— is a radical of formula (a-1) or(a-2), in particular (a-1); or d) R² is aryl, C₃₋₇cycloalkyl orC₁₋₁₂alkyl wherein C₁₋₁₂alkyl may optionally be substituted with 1 ormore substituents selected from hydroxy, aryl, aryloxy, substituted orunsubstituted C₁₋₁₄heterocycle, hydroxycarbonyl, hydroxyC₁₋₆alkyloxy, orarylC₁₋₆alkylthio; or e) R³ is aryl; —NR⁵R⁶; substituted orunsubstituted C₁₋₁₄heterocycle or C₂₋₄alkenediyl substituted with one ormore substituents selected from aryl, and a substituted or unsubstitutedC₁₋₁₄heterocycle; or f) R⁴ is hydrogen or C₁₋₆alkyl; or g) R⁵, R⁶, R⁷,R⁸, R⁹, or X are defined as above.
 3. A compound according to claim 1wherein; a) L¹ is R¹—Y— wherein R¹ is hydrogen, substituted orunsubstituted phenyl, benzodioxolyl, pyridinyl or pyridinyl substitutedwith one or more substituents selected from C₁₋₆alkyl, hydroxy, halo,cyano, and C₁₋₆alkyloxycarbonyl and wherein Y is C₁₋₄alkanediyl or adirect bond; or b) L² is R¹—Y— wherein R¹ is hydrogen, cyano,substituted or unsubstituted phenyl and wherein Y is C₁₋₄alkanediyl or adirect bond; or c) ═Z¹—Z²═Z³— is a radical of formula (a-1); d) X isSO₂, C(═O) or a direct bond; or e) R² is aryl, C₁₋₁₂alkyl or C₁₋₁₂alkylsubstituted with one or more substituents selected from aryl and asubstituted or unsubstituted C₁₋₁₄heterocycle; or f) R³ is aryl, asubstituted or unsubstituted C₁₋₁₄heterocycle, or a C₂₋₄alkenediylsubstituted with one or more aryl; or g) R⁴ is hydrogen; or h) R⁵, R⁶,R⁷, R⁸ or R⁹ are defined as above.
 4. A compound according to claim 1,wherein L¹ is R¹—Y— with R¹ is hydrogen, phenyl, pyridinyl, phenylsubstituted with one or more substituents selected from halo, nitro,cyano, C₁₋₁₂alkyl, and C₁₋₁₂alkyloxy or pyridinyl substituted with oneor more substituents selected from C₁₋₆alkyl and cyano and wherein Y isC₁₋₄alkanediyl; L² is R¹—Y— with R¹ is hydrogen or cyano and wherein Yis C₁₋₄alkanediyl or a direct bond; ═Z¹—Z²═Z³— is a radical of formula(a-1); R² is aryl, C₁₋₁₂alkyl or C₁₋₁₂alkyl substituted with one or moresubstituents selected from aryl, and a substituted or unsubstitutedC₁₋₁₄heterocycle; R³ is aryl, a substituted or unsubstitutedC₁₋₁₄heterocycle selected from quinoline, quinoxaline, benzofuran,furan, dihydrobenzofuran, benzopyran, pyridine, benzothiophene,pyrrolidine, indene, benzodioxolane and thiophene, or a C₂₋₄alkenediylsubstituted with one or more substituents selected from naphthyl, phenyland phenyl substituted with one or more substituents selected from halo,cyano, nitro, substituted or unsubstituted phenyl, phenyloxy,trifluoromethyl, methoxy, thienyl, trifluoromethyloxy, morpholinyl andC₁₋₁₂alkyl; R⁴ is hydrogen.
 5. A compound according to claim 1represented by formula (I-a)

or their prodrugs, N-oxides, addition salts, quaternary amities andstereochemically isomeric forms, wherein X is SO₂, (CH₂)_(n), C(═O) or adirect bond; Y is C₁₋₄alkanediyl, C₂₋₄alkenediyl, C₂₋₄alkynediyl orC(═O); ═Z¹—Z²═Z³— represents a radical of formula═N—N═CH—  (a-1)═N—CH═N—  (a-2) or═CH—N═N—  (a-3); n is 1 to 4; R¹ is aryl or a substituted orunsubstituted C₁₋₁₄heterocycle; R² is aryl, C₃₋₇cycloalkyl or C₁₋₁₂alkylwherein C₃₋₇cycloalkyl and C₁₋₁₂alkyl may optionally be substituted with1 or more substituents selected from hydroxy, aryl, aryloxy, asubstituted or unsubstituted C₁₋₁₄heterocycle, C₃₋₇cycloalkyl,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, hydroxyC₁₋₆alkyl,hydroxyC₁₋₆alkyloxy, hydroxyC₁₋₆alkylthio or arylC₁₋₆alkylthio; R³ isaryl or substituted or unsubstituted C₁₋₁₄heterocycle; R⁴ is hydrogen,aryl, C₃₋₄cycloalkyl or C₁₋₆alkyl optionally substituted withC₃₋₇cycloalkyl, hydroxycarbonyl, C₁₋₄alkyloxycarbonyl or aryl; aryl isnaphthyl or phenyl each of which may optionally be substituted with oneor more substituents selected from trifluoromethyl, trifluoromethyloxy,halo, cyano, nitro, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, phenylC₁₋₆alkyl,phenylC₁₋₆alkyloxy, phenyloxy, phenylcarbonyl, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino,C₁₋₆alkylcarbonylamino, substituted or unsubstituted phenyl or aC₁₋₁₄heterocycle.
 6. A compound according to claim 5 wherein; Y isC₁₋₄alkanediyl, C₁₋₄alkynediyl or C(═); ═Z¹—Z²═Z³— is a radical offormula (a-1) or (a-2), in particular (a-1); R¹ is phenyl, benzodioxolylor pyridinyl wherein said phenyl may optionally be substituted with oneor more substituents selected from halo, nitro, cyano, C₁₋₁₂alkyl,C₁₋₁₂alkyloxy, C₁₋₆alkyloxycarbonyl, trifluoromethyl; and wherein saidpyridinyl may optionally be substituted with one or more substituentsselected from C₁₋₆alkyl, hydroxy, halo, cyano, C₁₋₆alkyloxycarbonyl; R²is aryl, C₃₋₇cycloalkyl or C₁₋₁₂alkyl wherein C₁₋₁₂alkyl may optionallybe substituted with 1 or more substituents selected from hydroxy, aryl,aryloxy, substituted or unsubstituted C₁₋₁₄heterocycle, hydroxycarbonyl,hydroxyC₁₋₆alkyloxy, or arylC₁₋₆alkylthio; R³ is aryl or a substitutedor unsubstituted C₁₋₁₄heterocycle selected from triazole, thiophene,quinoline, benzothiazole, quinoxaline, imidazole, benzimidazole,pyridine, pyrimidine and triazine; R⁴ is hydrogen.
 7. A monosubstitutedtriazole of formula

wherein R², R³, R⁴, X and ═Z¹—Z²═Z³— are as defined in claim
 1. 8. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier, and as active ingredient a therapeutically effective amount ofa compound as described in claim
 1. 9. A process for preparing apharmaceutical composition wherein a therapeutically effective amount ofa compound as claimed in claim 1 is intimately mixed with apharmaceutically acceptable carrier.
 10. A process for the preparationof a compound of formula (I) as defined in claim 1 wherein ═Z¹—Z²═Z³—represents a radical of formula (a-1), L¹ and L² are R¹—Y— whereby Y isC₁₋₄alkanediyl for L¹, and whereby Y is C₁₋₄alkanediyl or a direct bondfor L², by reacting a compound of formula (IV) wherein W¹ is a suitableleaving group with an amino derivative of formula J-4 optionally in asuitable solvent under an inert reaction atmosphere, and optionally inthe presence of a base, or other reagents like coupling agents orreducing agents,

and thereafter, or simultaneously therewith, effecting one or more ofthe following optional conversions: (i) when the compound of formula (I)is formed, converting it into another compound of formula (I) havingdifferent values of L¹, L², R², R³, and R⁴ by treatment with anappropriate reagent and/or under suitable conditions; (ii) removing anyremaining protecting groups; (iii) when the compound of formula (I) isformed, converting into a prodrug, N-oxide, addition salt, quaternaryamine or stereochemically isomeric form thereof.